LuPone was born April 21, 1949, in Northport, New York, on Long Island, the daughter of Angela Louise (née Patti), a college library administrator, and Orlando Joseph LuPone, a school administrator.[3] Her great-grand-aunt was the celebrated 19th-century opera singer Adelina Patti.[4] Her older brother Robert LuPone is an actor, dancer, and director who originated the role of Zach the director in A Chorus Line.

In 1976, producerDavid Merrick hired LuPone as a replacement to play Genevieve, the title role of the troubled pre-Broadway production of The Baker's Wife. The production toured at length but Merrick deemed it unworthy of Broadway and it closed out of town.[13]

Since 1977, LuPone has been a frequent collaborator with David Mamet, appearing in his plays The Woods, All Men are Whores, The Blue Hour, The Water Engine (1978),[14]Edmond and The Old Neighborhood (1997).[15] The New York Times reviewer wrote of LuPone in The Old Neighborhood "Those who know Ms. LuPone only as a musical comedy star will be stunned by the naturalistic fire she delivers here. As Jolly, a part inspired by Mr. Mamet's real-life sister and his realized female character, Ms. LuPone finds conflicting layers of past and present selves in practically every line. She emerges as both loving matriarch and wounded adolescent, sentimental and devastatingly clear-eyed."[16] In 1978, she appeared in the Broadway musical adaptation of Studs Terkel’s Working, which ran for only 24 performances.[17]

In 1979 LuPone starred in the original Broadway production of Evita, the musical based on the life of Eva Perón, composed by Andrew Lloyd Webber and Tim Rice, and directed by Harold Prince.[18] Although LuPone was hailed by critics, she has since said that her time in Evita was not an enjoyable one. In a 2007 interview, she stated " 'Evita' was the worst experience of my life," she said. "I was screaming my way through a part that could only have been written by a man who hates women. And I had no support from the producers, who wanted a star performance onstage but treated me as an unknown backstage. It was like Beirut, and I fought like a banshee."[19] Despite the trouble, LuPone won her first Tony Award for Best Actress in a Musical.[20] LuPone and her co-star, Mandy Patinkin, remained close friends both on and off the stage.

In May 1983, founding alumni of The Acting Company reunited for an off-Broadway revival of Marc Blitzstein’s landmark labor musical The Cradle Will Rock at the American Place Theater. It was narrated by John Houseman, with LuPone in the roles of Moll and Sister Mister.[21] The production premiered at The Acting Company's summer residence at Chautauqua Institution, toured the United States, including an engagement at the Highland Park, Illinois' Ravinia Festival in 1984, and played London's West End.

In 1993, LuPone returned to London to create the role of Norma Desmond in the original production of Andrew Lloyd Webber’s Sunset Boulevard at the Adelphi Theater. There was much anticipation of LuPone appearing in another Lloyd Webber musical, the first since her performance in Evita. Her time in the show was difficult and she was abruptly fired by Lloyd Webber and replaced by Glenn Close who opened the show in Los Angeles and eventually on Broadway.[29][30]

She returned to Broadway in October 2005, to star as Mrs. Lovett in John Doyle's new Broadway production of Sweeney Todd. In this radically different interpretation of the musical, the ten actors on stage also served as the show's orchestra, and LuPone played the tuba and the orchestra bells as well as vocally performing the score.[35] For her performance, she received a Tony Award nomination as well as a Golden Icon Award for Best Female Musical Theater Performance.[36] In August 2006, LuPone took a three-week leave from Sweeney in order to play Rose in Lonny Price's production of Gypsy at Ravinia.[34]Sweeney Todd closed in September 2006.

Following the Ravinia Festival production of Gypsy, LuPone and author Arthur Laurents mended a decade-long rift and she was cast in the City Center Encores! Summer Stars production of the show. Laurents directed LuPone in Gypsy for a 22 performance run (July 9, 2007 – July 29, 2007) at City Center.[39] This production of Gypsy then transferred to Broadway, opening March 27, 2008 at the St. James Theatre.[40] LuPone won the Outer Critics Circle Award, Drama League Award, Drama Desk Award, and Tony Award for her performance in Gypsy.[41][42] It closed on January 11, 2009.

In 2010, LuPone created the role of Lucia in the original Broadway production of Women on the Verge of a Nervous Breakdown, which opened at the Belasco Theater on November 4, 2010, and closed on January 2, 2011, after 23 previews and 69 regular performances. LuPone was nominated for a Tony Award, Drama Desk Award, and an Outer Critics Circle Award for her performance.

In 2011, LuPone played the role of Joanne in a four-night limited engagement concert production of Stephen Sondheim's 1970 musical Company at the New York Philharmonic, conducted by Sondheim expert Paul Gemignani. The production starred Neil Patrick Harris as Bobby. Harris had previously worked with LuPone in the 2000 and 2001 concert productions of Sweeney Todd. The cast of Company performed the song "Side by Side by Side" at the 65th Tony Awards on June 12, 2011.

LuPone concluded a 63-performance Broadway engagement of her concert with former Evita co-star Mandy Patinkin, entitled An Evening with Patti LuPone and Mandy Patinkin. The run started on November 21, 2011 at the Ethel Barrymore Theater, and ended on January 13, 2012.[45]

In the fall of 2012 LuPone appeared with Debra Winger in David Mamet's new play The Anarchist. Despite the play receiving less than stellar reviews from critics, LuPone received widespread praise for her role as Cathy.

LuPone performs regularly in her solo shows Matters of the Heart; Coulda, Woulda, Shoulda; and The Lady With the Torch[47] which sold out at Carnegie Hall. For example, she performed her one-woman show The Gypsy In My Soul at the Caramoor Fall Festival, New York, in September 2010.[48]

She also appears at venues across North America in concerts with Mandy Patinkin, at such venues as the Mayo Center for the Performing Arts in September 2010.[49][50]

She is appearing as the inaugural act at a new cabaret space, 54 Below, in New York City in June 2012. According to the New York Times reviewer, "Nowadays Ms. LuPone generates more raw excitement than any other performer on the Broadway and cabaret axis, with the possible exception of Liza Minnelli.... And her brilliant show, conceived and directed by her longtime collaborator, Scott Wittman, deserves many lives, perhaps even a Broadway run in an expanded edition. It certifies Ms. LuPone's place in the lineage of quirky international chanteuses like Lotte Lenya, Marlene Dietrich and Edith Piaf, who, like Ms. LuPone, conquered show business with forceful, outsize personalities while playing by their own musical rules."[51]

She also appeared as the inaugural act at the Sharon L. Morse Entertainment Center in The Villages, Florida on April 30, 2015, to a sold out audience of residents mainly 55 years-of-age and older.[52]

LuPone's TV work also included a recurring role on her cousin Tom Fontana's HBO series in its final season, Oz (2003).[60] She appeared as herself on a February 2005 episode of Will & Grace.[61] She also appeared on the series Ugly Betty in March 2007 as the mother of Marc St. James (played by Michael Urie).[62] LuPone had a recurring guest role as Frank Rossitano's mother on 30 Rock. LuPone appeared as herself in the season two finale of the television series Glee.

LuPone opposes recording, photographs, and other electronic distractions in live theatre. "Where's the elegance?" she asked in a blog post on her official site. "I mean, I'm glad they show up because God knows it's a dying art form and I guess I'm glad they're all comfortable, sleeping, eating and drinking, things they should be doing at home and in a restaurant. But it's just not done in the theater or shouldn't be." LuPone has been the subject of some controversy due to the bluntness of her statements regarding this matter.[68]

A related incident occurred at the second to last performance of Gypsy on January 10, 2009. LuPone, irritated by flash photography, stopped in the middle of "Rose's Turn" and loudly demanded that the interloper be removed from the theatre. After he was removed, LuPone restarted her number. The audience applauded her stance.[69][70] The event was recorded by another audience member, who released it on YouTube.[71] She later stated that such distractions drive "people in the audience nuts. They can't concentrate on the stage if, in their peripheral vision, they're seeing texting, they're seeing cameras, they're listening to phone calls. How can we do our job if the audience is distracted?", and also mentioned that "the interesting thing is I'm not the first one that's done it".[72]

On July 8, 2015, during the second act of Shows for Days at the Lincoln Center Theater, LuPone grabbed an audience member's cellphone while leaving the stage as the audience member had been using their phone during the play. It was returned after the show. LuPone stated:[73]

We work hard on stage to create a world that is being totally destroyed by a few, rude, self-absorbed and inconsiderate audience members who are controlled by their phones. They cannot put them down. When a phone goes off or when a LED screen can be seen in the dark it ruins the experience for everyone else - the majority of the audience at that performance and the actors on stage. I am so defeated by this issue that I seriously question whether I want to work on stage anymore. Now I’m putting battle gear on over my costume to marshal the audience as well as perform.

LuPone wrote a memoir, recounting her life and career from childhood to the present, which was released in September 2010. It was simply titled Patti LuPone: A Memoir, which was, according to LuPone, the winner of the competition she held to name the book.[74][75]

A live concert special film, "An Evening with Patti LuPone", was filmed in July 2012 and released in November 2012 on SethTv.com with 104 minutes of Patti LuPone songs and stories with host Seth Rudetsky.[83]